CA2818545C - Pyrrolopyridines et pyrrolopyrimidines a substitution heterocyclique utilisees en tant qu'inhibiteurs des jak - Google Patents
Pyrrolopyridines et pyrrolopyrimidines a substitution heterocyclique utilisees en tant qu'inhibiteurs des jak Download PDFInfo
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- CA2818545C CA2818545C CA2818545A CA2818545A CA2818545C CA 2818545 C CA2818545 C CA 2818545C CA 2818545 A CA2818545 A CA 2818545A CA 2818545 A CA2818545 A CA 2818545A CA 2818545 C CA2818545 C CA 2818545C
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- CA
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- Prior art keywords
- alkyl
- independently selected
- heterocycloalkyl
- cycloalkyl
- pyrazol
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- 150000005255 pyrrolopyridines Chemical class 0.000 title abstract description 4
- 150000004944 pyrrolopyrimidines Chemical class 0.000 title abstract description 4
- 229940122245 Janus kinase inhibitor Drugs 0.000 title description 26
- 239000000203 mixture Substances 0.000 claims abstract description 126
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 40
- 201000011510 cancer Diseases 0.000 claims abstract description 27
- 230000000694 effects Effects 0.000 claims abstract description 27
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 17
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 234
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 139
- 150000003839 salts Chemical class 0.000 claims description 78
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 76
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 72
- -1 di-C1-4-alkylamino Chemical group 0.000 claims description 64
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 49
- 125000001072 heteroaryl group Chemical group 0.000 claims description 45
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 44
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 36
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 claims description 28
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 24
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 24
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 claims description 18
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Chemical group 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 201000004681 Psoriasis Diseases 0.000 claims description 12
- 206010028537 myelofibrosis Diseases 0.000 claims description 12
- 208000003476 primary myelofibrosis Diseases 0.000 claims description 11
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 10
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 10
- 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 9
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 9
- 208000037244 polycythemia vera Diseases 0.000 claims description 9
- 208000017520 skin disease Diseases 0.000 claims description 9
- 208000006386 Bone Resorption Diseases 0.000 claims description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 8
- 230000024279 bone resorption Effects 0.000 claims description 8
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 210000000056 organ Anatomy 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 206010012442 Dermatitis contact Diseases 0.000 claims description 6
- 206010070834 Sensitisation Diseases 0.000 claims description 6
- 206010052779 Transplant rejections Diseases 0.000 claims description 6
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 208000019664 bone resorption disease Diseases 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 230000008313 sensitization Effects 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 5
- 208000009525 Myocarditis Diseases 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 208000010247 contact dermatitis Diseases 0.000 claims description 5
- 208000010201 Exanthema Diseases 0.000 claims description 4
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 claims description 4
- 206010070835 Skin sensitisation Diseases 0.000 claims description 4
- 201000008736 Systemic mastocytosis Diseases 0.000 claims description 4
- 230000001363 autoimmune Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 201000005884 exanthem Diseases 0.000 claims description 4
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
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- 231100000370 skin sensitisation Toxicity 0.000 claims description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 claims description 3
- 108060003951 Immunoglobulin Proteins 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
- 208000010668 atopic eczema Diseases 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- 102000018358 immunoglobulin Human genes 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 206010028417 myasthenia gravis Diseases 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 231100000046 skin rash Toxicity 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000005024 Castleman disease Diseases 0.000 claims description 2
- 206010073069 Hepatic cancer Diseases 0.000 claims description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010028561 Myeloid metaplasia Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 206010040880 Skin irritation Diseases 0.000 claims description 2
- 208000024799 Thyroid disease Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 230000000172 allergic effect Effects 0.000 claims description 2
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 claims description 2
- 230000003054 hormonal effect Effects 0.000 claims description 2
- 238000001794 hormone therapy Methods 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 230000036556 skin irritation Effects 0.000 claims description 2
- 231100000475 skin irritation Toxicity 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 26
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 1
- YOCDOOSCOIMHQR-UHFFFAOYSA-N 3-[1-[3-cyano-2-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propyl]piperidin-4-yl]oxy-5-fluoro-n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 YOCDOOSCOIMHQR-UHFFFAOYSA-N 0.000 claims 1
- JSLBOJRZTSCDGQ-UHFFFAOYSA-N 3-[1-[3-cyano-2-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propyl]piperidin-4-yl]oxy-5-fluoro-n-(2-morpholin-4-ylethyl)benzamide Chemical compound C=1C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC=1C(=O)NCCN1CCOCC1 JSLBOJRZTSCDGQ-UHFFFAOYSA-N 0.000 claims 1
- SEUOHDHHDNZXHB-UHFFFAOYSA-N 3-[1-[3-cyano-2-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propyl]piperidin-4-yl]oxy-5-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 SEUOHDHHDNZXHB-UHFFFAOYSA-N 0.000 claims 1
- JDOHXRZTBUPSKP-UHFFFAOYSA-N 3-[1-[3-cyano-2-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propyl]piperidin-4-yl]oxy-5-fluoro-n-propan-2-ylbenzamide Chemical compound CC(C)NC(=O)C1=CC(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 JDOHXRZTBUPSKP-UHFFFAOYSA-N 0.000 claims 1
- SEOQJUILHDSYGC-UHFFFAOYSA-N 3-[1-[3-cyano-2-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propyl]piperidin-4-yl]oxy-5-fluorobenzonitrile Chemical compound N#CC1=CC(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 SEOQJUILHDSYGC-UHFFFAOYSA-N 0.000 claims 1
- FXSPWQXHRRYQEM-UHFFFAOYSA-N 3-[1-[3-cyano-2-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propyl]piperidin-4-yl]oxy-n-cyclopropyl-5-fluorobenzamide Chemical compound C=1C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC=1C(=O)NC1CC1 FXSPWQXHRRYQEM-UHFFFAOYSA-N 0.000 claims 1
- XXTMYVZUSKBQFP-UHFFFAOYSA-N 3-[1-[3-cyano-2-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propyl]piperidin-4-yl]oxy-n-ethyl-5-fluorobenzamide Chemical compound CCNC(=O)C1=CC(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 XXTMYVZUSKBQFP-UHFFFAOYSA-N 0.000 claims 1
- DSBQTKIXIKXASN-UHFFFAOYSA-N 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]-4-[4-(2,3,5-trifluorophenoxy)piperidin-1-yl]butanenitrile Chemical compound FC1=CC(F)=C(F)C(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 DSBQTKIXIKXASN-UHFFFAOYSA-N 0.000 claims 1
- MHMVFXJDZGWALF-UHFFFAOYSA-N 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]-4-[4-(3,4,5-trifluorophenoxy)piperidin-1-yl]butanenitrile Chemical compound FC1=C(F)C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 MHMVFXJDZGWALF-UHFFFAOYSA-N 0.000 claims 1
- URVMIMNVUGRBSP-UHFFFAOYSA-N 4-[3-fluoro-4-[3-fluoro-5-[(2-methylpyrrolidin-1-yl)methyl]phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound CC1CCCN1CC1=CC(F)=CC(OC2C(CN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)F)=C1 URVMIMNVUGRBSP-UHFFFAOYSA-N 0.000 claims 1
- URVMIMNVUGRBSP-NUIGPVJISA-N 4-[3-fluoro-4-[3-fluoro-5-[[(2r)-2-methylpyrrolidin-1-yl]methyl]phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C[C@@H]1CCCN1CC1=CC(F)=CC(OC2C(CN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)F)=C1 URVMIMNVUGRBSP-NUIGPVJISA-N 0.000 claims 1
- URVMIMNVUGRBSP-OZFFGNQVSA-N 4-[3-fluoro-4-[3-fluoro-5-[[(2s)-2-methylpyrrolidin-1-yl]methyl]phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C[C@H]1CCCN1CC1=CC(F)=CC(OC2C(CN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)F)=C1 URVMIMNVUGRBSP-OZFFGNQVSA-N 0.000 claims 1
- VICMTEUORBGTEP-UHFFFAOYSA-N 4-[4-(3,5-difluorophenoxy)piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound FC1=CC(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 VICMTEUORBGTEP-UHFFFAOYSA-N 0.000 claims 1
- GMMRSVRQQIOIKN-UHFFFAOYSA-N 4-[4-(3-chloro-5-fluorophenoxy)piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound FC1=CC(Cl)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 GMMRSVRQQIOIKN-UHFFFAOYSA-N 0.000 claims 1
- ZIADBVSZLLNJPH-UHFFFAOYSA-N 4-[4-[3-(3,3-difluoropyrrolidine-1-carbonyl)-5-fluorophenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC=1C(=O)N1CCC(F)(F)C1 ZIADBVSZLLNJPH-UHFFFAOYSA-N 0.000 claims 1
- IHDYBGHYDAWWIY-UHFFFAOYSA-N 4-[4-[3-(azetidin-1-ylmethyl)-5-fluorophenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC(F)=CC=1CN1CCC1 IHDYBGHYDAWWIY-UHFFFAOYSA-N 0.000 claims 1
- CNOWJAOUZKWKNX-UHFFFAOYSA-N 4-[4-[3-[(3,3-difluoropyrrolidin-1-yl)methyl]-5-fluorophenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC(F)=CC=1CN1CCC(F)(F)C1 CNOWJAOUZKWKNX-UHFFFAOYSA-N 0.000 claims 1
- JQTLRRGIBOTHQB-UHFFFAOYSA-N 4-[4-[3-[(cyclobutylamino)methyl]-5-fluorophenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC(F)=CC=1CNC1CCC1 JQTLRRGIBOTHQB-UHFFFAOYSA-N 0.000 claims 1
- ATYHEOHLMAPLAD-UHFFFAOYSA-N 4-[4-[3-[[cyclopropyl(methyl)amino]methyl]-5-fluorophenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC=1CN(C)C1CC1 ATYHEOHLMAPLAD-UHFFFAOYSA-N 0.000 claims 1
- KOCNCGFWFXFSOT-UHFFFAOYSA-N 4-[4-[3-fluoro-5-(morpholin-4-ylmethyl)phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC(F)=CC=1CN1CCOCC1 KOCNCGFWFXFSOT-UHFFFAOYSA-N 0.000 claims 1
- OTRBCNASPJWAMF-UHFFFAOYSA-N 4-[4-[3-fluoro-5-(morpholine-4-carbonyl)phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC=1C(=O)N1CCOCC1 OTRBCNASPJWAMF-UHFFFAOYSA-N 0.000 claims 1
- VLHNDRNFNDBLFO-UHFFFAOYSA-N 4-[4-[3-fluoro-5-(piperidine-1-carbonyl)phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC=1C(=O)N1CCCCC1 VLHNDRNFNDBLFO-UHFFFAOYSA-N 0.000 claims 1
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- IYDSFYUXKVHDQA-UHFFFAOYSA-N 4-[4-[3-fluoro-5-(pyrrolidine-1-carbonyl)phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound C=1C(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=CC=1C(=O)N1CCCC1 IYDSFYUXKVHDQA-UHFFFAOYSA-N 0.000 claims 1
- DBVSFRQQMBDWBG-UHFFFAOYSA-N 4-[4-[3-fluoro-5-(trifluoromethyl)phenoxy]piperidin-1-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]butanenitrile Chemical compound FC(F)(F)C1=CC(F)=CC(OC2CCN(CC(CC#N)N3N=CC(=C3)C=3C=4C=CNC=4N=CN=3)CC2)=C1 DBVSFRQQMBDWBG-UHFFFAOYSA-N 0.000 claims 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229940055059 vexol Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- BICRTLVBTLFLRD-PTWUADNWSA-N voclosporin Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C=C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O BICRTLVBTLFLRD-PTWUADNWSA-N 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
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- YKPUWZUDDOIDPM-VURMDHGXSA-N zucapsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C/C(C)C)=CC=C1O YKPUWZUDDOIDPM-VURMDHGXSA-N 0.000 description 1
- 229960002860 zucapsaicin Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
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Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Immunology (AREA)
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- Hematology (AREA)
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- Oncology (AREA)
- Transplantation (AREA)
- Neurosurgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
La présente invention concerne des pyrrolopyridines à substitution hétérocyclique et des pyrrolopyrimidines de formule I : dans laquelle X, Y, Z, L, A, R5, n, m et r ont la signification indiquée dans la description, ainsi que des compositions en contenant et leurs méthodes d'utilisation. Lesdits composés modulent l'activité des Janus kinases (JAK) et peuvent être utilisés dans le cadre du traitement de maladies associées à l'activité des JAK dont, notamment, les troubles inflammatoires, les maladies auto-immunes, les cancers et d'autres maladies.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41561710P | 2010-11-19 | 2010-11-19 | |
US61/415,617 | 2010-11-19 | ||
PCT/US2011/061351 WO2012068440A1 (fr) | 2010-11-19 | 2011-11-18 | Pyrrolopyridines et pyrrolopyrimidines à substitution hétérocyclique utilisées en tant qu'inhibiteurs des jak |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2818545A1 CA2818545A1 (fr) | 2012-05-24 |
CA2818545C true CA2818545C (fr) | 2019-04-16 |
Family
ID=45217696
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2818545A Active CA2818545C (fr) | 2010-11-19 | 2011-11-18 | Pyrrolopyridines et pyrrolopyrimidines a substitution heterocyclique utilisees en tant qu'inhibiteurs des jak |
Country Status (7)
Country | Link |
---|---|
US (1) | US9034884B2 (fr) |
EP (1) | EP2640725B1 (fr) |
JP (1) | JP5917544B2 (fr) |
CA (1) | CA2818545C (fr) |
ES (1) | ES2536415T3 (fr) |
HK (1) | HK1189877A1 (fr) |
WO (1) | WO2012068440A1 (fr) |
Families Citing this family (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2611588T3 (es) | 2005-12-13 | 2017-05-09 | Incyte Holdings Corporation | Pirrolo[2,3-b]piridinas y pirrolo[2,3-b]pirimidinas sustituidas con heteroarilo como inhibidores de quinasas Janus |
LT3070090T (lt) | 2007-06-13 | 2019-06-25 | Incyte Holdings Corporation | Janus kinazės inhibitoriaus (r)-3-(4-(7h-pirol[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)-3-ciklopentilpropannitrilo druskų panaudojimas |
CL2008001709A1 (es) | 2007-06-13 | 2008-11-03 | Incyte Corp | Compuestos derivados de pirrolo [2,3-b]pirimidina, moduladores de quinasas jak; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como cancer, psoriasis, artritis reumatoide, entre otras. |
JOP20190230A1 (ar) | 2009-01-15 | 2017-06-16 | Incyte Corp | طرق لاصلاح مثبطات انزيم jak و المركبات الوسيطة المتعلقة به |
EA025520B1 (ru) * | 2009-05-22 | 2017-01-30 | Инсайт Холдингс Корпорейшн | N-(ГЕТЕРО)АРИЛПИРРОЛИДИНОВЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛ-4-ИЛ-ПИРРОЛО[2,3-d]ПИРИМИДИНОВ И ПИРРОЛ-3-ИЛ-ПИРРОЛО[2,3-d]ПИРИМИДИНОВ В КАЧЕСТВЕ ИНГИБИТОРОВ ЯНУС-КИНАЗЫ |
EA020494B1 (ru) | 2009-05-22 | 2014-11-28 | Инсайт Корпорейшн | 3-[4-(7H-ПИРРОЛО[2,3-d]ПИРИМИДИН-4-ИЛ)-1H-ПИРАЗОЛ-1-ИЛ]ОКТАН- ИЛИ ГЕПТАННИТРИЛ КАК JAK-ИНГИБИТОРЫ |
CN104945420A (zh) | 2009-06-29 | 2015-09-30 | 因塞特公司 | 作为pi3k抑制剂的嘧啶酮类 |
TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
NZ602313A (en) | 2010-03-10 | 2014-08-29 | Incyte Corp | Piperidin-4-yl azetidine derivatives as jak1 inhibitors |
ME02445B (fr) | 2010-05-21 | 2016-09-20 | Incyte Holdings Corp | Formulation topique pour inhibiteur de jak |
WO2012068440A1 (fr) | 2010-11-19 | 2012-05-24 | Incyte Corporation | Pyrrolopyridines et pyrrolopyrimidines à substitution hétérocyclique utilisées en tant qu'inhibiteurs des jak |
CA2818542A1 (fr) | 2010-11-19 | 2012-05-24 | Incyte Corporation | Derives pyrrolopyridine et pyrrolopyrimidine a substitution cyclobutyle utilises comme inhibiteurs des jak |
AR084366A1 (es) | 2010-12-20 | 2013-05-08 | Incyte Corp | N-(1-(fenil sustituido)etil)-9h-purin-6-aminas como inhibidores de pi3k |
CN103732226B (zh) | 2011-02-18 | 2016-01-06 | 诺瓦提斯药物公司 | mTOR/JAK抑制剂组合疗法 |
WO2012177606A1 (fr) | 2011-06-20 | 2012-12-27 | Incyte Corporation | Dérivés d'azétidinyl-phényl-, de pyridyl- ou de pyrazinyl-carboxamide en tant qu'inhibiteurs des jak |
JP2014521725A (ja) | 2011-08-10 | 2014-08-28 | ノバルティス・ファルマ・アクチェンゲゼルシャフト | JAKPI3K/mTOR併用療法 |
TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為jak抑制劑之環己基氮雜環丁烷衍生物 |
HUE043703T2 (hu) | 2011-09-02 | 2019-09-30 | Incyte Holdings Corp | Heterociklusos aminok PI3K inhibitorokként |
UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
AR090548A1 (es) | 2012-04-02 | 2014-11-19 | Incyte Corp | Azaheterociclobencilaminas biciclicas como inhibidores de pi3k |
US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
CN104918945B (zh) | 2012-11-01 | 2018-01-05 | 因赛特公司 | 作为jak抑制剂的三环稠合噻吩衍生物 |
LT2919766T (lt) | 2012-11-15 | 2021-09-27 | Incyte Holdings Corporation | Ruksolitinibo pailginto atpalaidavimo vaisto formos |
JP6437452B2 (ja) | 2013-01-14 | 2018-12-12 | インサイト・ホールディングス・コーポレイションIncyte Holdings Corporation | Pimキナーゼ阻害剤として有用な二環式芳香族カルボキサミド化合物 |
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JP2014521725A (ja) | 2011-08-10 | 2014-08-28 | ノバルティス・ファルマ・アクチェンゲゼルシャフト | JAKPI3K/mTOR併用療法 |
TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為jak抑制劑之環己基氮雜環丁烷衍生物 |
UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
-
2011
- 2011-11-18 WO PCT/US2011/061351 patent/WO2012068440A1/fr active Application Filing
- 2011-11-18 JP JP2013540045A patent/JP5917544B2/ja active Active
- 2011-11-18 CA CA2818545A patent/CA2818545C/fr active Active
- 2011-11-18 ES ES11793604.7T patent/ES2536415T3/es active Active
- 2011-11-18 US US13/300,137 patent/US9034884B2/en active Active
- 2011-11-18 EP EP11793604.7A patent/EP2640725B1/fr active Active
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2014
- 2014-03-14 HK HK14102599.5A patent/HK1189877A1/xx unknown
Also Published As
Publication number | Publication date |
---|---|
EP2640725B1 (fr) | 2015-01-07 |
WO2012068440A1 (fr) | 2012-05-24 |
JP2013543007A (ja) | 2013-11-28 |
ES2536415T3 (es) | 2015-05-25 |
EP2640725A1 (fr) | 2013-09-25 |
CA2818545A1 (fr) | 2012-05-24 |
US9034884B2 (en) | 2015-05-19 |
HK1189877A1 (en) | 2014-06-20 |
JP5917544B2 (ja) | 2016-05-18 |
US20120149682A1 (en) | 2012-06-14 |
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